Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties have been cloned. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events.
WO99/47497 discloses carboxylic acids and acylsulfonamides compounds as prostaglandin-receptor antagonists. Although heteroaryl compounds synthesized are described in WO00/64888, it relates to peroxisome proliferataor-activated receptors (PPAR) ligands. Further, pyrazole compounds synthesized for different uses are described in WO98/56377, such as treatment of cytokine mediated diseases.
The invention addresses the problem of providing EP4 receptor modulators (e.g., agonists and antagonists) which have improved EP4 receptor modulating activities (e.g., angonist or antagonist activities).